Cellular immune responses play a crucial role in controlling viral replication in HIV- infected individuals. However, HIV virus adopts numerous mechanisms to evade the immune system and the host ultimately fails to control the viral replication leading to development of AIDS. Chronic inflammation and ongoing viral replication may lead to immune exhaustion, which is characterized by poor anti-viral responses against HIV. The major aims of the proposal are to 1) characterize the mechanisms of immune dysfunction and exhaustion during chronic HIV infection and 2) explore various strategies to restore or prevent immune exhaustion and improve viral control using the humanized mice model. The strategies include 1) targeting activation inhibitory molecules Tim-3 and PD-1 signaling by antibody blockade or shRNA knock down; and 2) targeting persistent type I IFN signaling to reduce the production of immunosuppressive factors that contribute to immune exhaustion. This study will identify underlying mechanisms for T cell exhaustion and provide key information for future immune based therapies aimed at treating chronic HIV infection.